The present invention provides oxazinoquinolone and thioxazinoquinolone derivatives having a ring connecting position 4 (N-4) and position 11 (C-11), and more specifically, provides compounds of formula (I) described herein below. These compounds are useful as antiviral agents, in particular, as agents against viruses of the herpes family.
The herpesviruses comprise a large family of double stranded DNA viruses. They are also a source of the most common viral illnesses in man. Eight of the herpes viruses, herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), varicella zoster virus (VZV), human cytomegalovirus (HCMV), epstein-Barr virus (EBV), and human herpes viruses 6, 7, and 8 (HHV-6, HHV-7, and (HHV-8), have been shown to infect humans.
HSV-1 and HSV-2 cause herpetic lesions on the lips and genitals, respectively. They also occasionally cause infections of the eye and encephalitis. HCMV causes birth defects in infants and a variety of diseases in immunocompromised patients such as retinitis, pneumonia, and gastrointestinal disease. VZV is the causitive agent of chicken pox and shingles. EBV causes infectious mononucleosis. It can also cause lymphomas in immunocompromised patients and has been associated with Burkitt""s lymphoma, nasopharyngeal carcinoma, and Hodgkins disease. HHV-6 is the causitive agent of roseola and may be associated with multiple sclerosis and chronic fatigue syndrome. HHV-7 disease association is unclear, but it may be involved in some cases of roseola. HHV-8 has been associated with Karposi""s sarcoma, body cavity based lymphomas, and multiple myeloma.
Due to the unique position of the para-substitutent on the N-phenylmethyl of formula I described herein below, compounds of the present invention demonstrate unexpected activity against the above reference herpesviral infections, particularly, human cytomegaloviral infection.
U.S. Pat. No. 5,792,774 discloses oxazino 1,4-dihydro-4-oxoquinolines useful for the treatment of a large number of diseases modulated by tissue necrosis factor (TNF) or phosphodiesterase IV, includng cytomegalovirus (CMV) infections.
U.S. Pat. No. 4,847,375 discloses 1,8-bridged 4-quinoline-3-carboxylic acids useful as antibacterial agents.
U.S. Pat. No. 5,583,135 discloses heterotricyclic derivatives having a strong immunomodulating activity, anti-inflammatory activity and anti-cancer activity.
The abstract of Japanese Patent JP 10324631-A discloses IgE antibody production inhibitor comprise a pyrido(1,2,3-del,4-benzoxazine or a pyrido (1,2,3,-de)-1,4-benzothiazine derivative.
PCT patent application, PCT/US00/21985 discloses oxazinoquinolones useful for the treatment of viral infections.
The present invention provides a compound of formula I, 
or a pharmaceutically acceptable salt, racemate, solvate, tautomer, optical isomer or prodrug derivative thereof wherein:
each X is independently O or S;
Y is Cl, F, Br, CN or NO2;
R1, R2, R3 and R4 are independently
a) hydrogen,
b) N3,
c) CN,
d) fluoro,
e) trifluoromethyl,
f) aryl,
g) het,
h) C1-8 alkyl, optionally substituted with R6 or OR7, or
i) R1 and R2 or R3 and R4 together with the carbon to which they are attached form C3-8cycloalkyl or het;
R5 is C1-8alkyl, which may be partially unsaturated and optionally substituted with one to three N3, halo, CN, R6 or R7;
R6 is
a) aryl,
b) het,
c) SOiR8,
d) OR8,
e) C(xe2x95x90O)OR8,
f) C(xe2x95x90O)R8, or
g) NR8R9;
R7 is
a) P(xe2x95x90O)(OR10)2,
b) CO(CH2)jCON(CH3)(CH2)kSO3xe2x88x92M+,
c) an amino acid,
d) C(xe2x95x90O)C1-6alkyl, optionally substituted by NR10R10, or
e) CO(CH2)nCO2H;
R8 and R9 are independently
a) hydrogen,
b) C3-8cycloalkyl,
c) aryl,
d) het, or
e) C1-8alkyl which is further optionally substituted with one or more aryl, het, halo, CN, CO2R10, SOiR10, OR10, NR10R10, CF3, or C3-8cycloalkyl;
R10 is
a) H or
b) C1-8alkyl, optionally substituted with OH or OC1-4alkyl;
R11 and R12 are independently
a) hydrogen,
b) halo,
c) NO2,
d) CN,
e) R6,
f) SOiNR8R9, or
g) C1-8alkyl, which may be partially unsaturated and optionally substituted with one to three N3, halo, CN, R6 or OR7;
aryl is
a phenyl radical, optionally fused with a saturated or unsaturated carbocyclic or heterocyclic ring; at each occurrence, aryl may be substituted with one or more halo, CN, CO2R10, SOiR10, OR10, NR10R10, CF3, C3-8cycloalkyl, or C1-4alkyl wherein C1-4alkyl is optionally substituted with OR10;
het is
a four-(4), five- (5), six- (6), or seven- (7) membered saturated or unsaturated heterocyclic ring having 1, 2, or 3 heteroatoms selected from the group consisting of O, S, and NW, wherein W is hydrogen, C1-4alkyl, C(xe2x95x90O)OC1-4alkyl or absent, wherein het is optionally fused with a benzene ring, a carbcyclic or a heterocyclic ring; at each occurrence, het may be substituted with one or more halo, CN, CO2R10, SOiR10, OR10, NR10R10, C1-4alkyl, CF3, C3-8cycloalkyl, oxo or oxine;
at each occurrence, a cycloalkyl group may be substituted with C1-4alkyl, OR10, oxo, oxine, or a spiro fused het;
i is 0, 1 or 2;
j is 1, 2, 3, 4, 5, or 6;
k is 1, 2, 3, 4, 5, or 6;
n is 1, 2, 3, 4, 5, or 6;
M is sodium, potassium, or lithium; and
with the following provisos:
a) at least one of R1, R2, R3 and R4 is other than hydrogen;
b) where R1, R2, R3 and R4 are independently C1-8 alkyl, at least one of the alkyl groups is substituted with R6 or OR7.
The present invention further provides a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier (the composition preferably comprises an effective antiviral amount of the compound or salt).
The present invention further provides a method of treating or preventing a herpesviral infection, comprising administering to a mammal in need of such treatment, a compound of formula (I) or a pharmaceutically acceptable salt thereof.
The present invention further provides a method of treating or preventing a herpesviral infection comprising administering orally, parenterally, topically, rectally, nasally, sublingually or transdermally an effective amount of a compound of claim 1.
The present invention further provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in medical treatment.
The present invention further provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof to prepare a medicament for treating or preventing a herpesviral infection in a mammal.
The present invention further provides a method for inhibiting a viral DNA polymerase, comprising contacting (in vitro or in vivo) the polymerase with an effective inhibitory amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.
The invention also provides novel intermediates and processes disclosed herein that are useful for preparing compounds of formula I.
The following definitions are used, unless otherwise described. Halo denotes fluoro, chloro, bromo, or iodo. Alkyl, alkoxy, etc. denote both straight and branched groups; but reference to an individual radical such as xe2x80x9cpropylxe2x80x9d embraces only the straight chain radical, a branched chain isomer such as xe2x80x9cisopropylxe2x80x9d being specifically referred to. When alkyl can be partially unsaturated, the alkyl chain may comprise one or more (e.g. 1, 2, 3, or 4) double or triple bonds in the chain.
The carbon atom content of various hydrocarbon-containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix Ci-j indicates a moiety of the integer xe2x80x9cixe2x80x9d to the integer xe2x80x9cjxe2x80x9d carbon atoms, inclusive. Thus, for example, (C1-3)alkyl refers to alkyl of one to three carbon atoms, inclusive, or methyl, ethyl, propyl and isopropyl, straight and branched forms thereof.
Aryl is a phenyl radical, optionally fused with a saturated or unsaturated carbocyclic or heterocyclic ring. At each occurrence, aryl may be substituted with one or more halo, CN, CO2R10, SOiR10, OR10, NR10R10, CF3, C3-8cycloalkyl, or C1-4alkyl wherein C1-4alkyl is optionally substituted with OR10.
Het is a four-(4), five-(5), six-(6), or seven-(7) membered saturated or unsaturated heterocyclic ring having 1, 2, or 3 heteroatoms selected from the group consisting of O, S, and NW, wherein W is hydrogen, C1-4alkyl, C(xe2x95x90O)OC1-4alkyl or absent, wherein het is optionally fused with a benzene ring, a carbcyclic or a heterocyclic ring. At each occurrence, het may be substituted with one or more halo, CN, CO2R10, SOiR10, OR10, NR10R10, C1-4alkyl, CF3, C3-8cycloalkyl, oxo or oxine;
The term xe2x80x9chetxe2x80x9d also includes piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, Nxe2x80x94C1-4alky substituted piperazinyl such as 4-methyl piperazinyl, pyrrolidinyl, pyridyl, imidazolyl, Nxe2x80x94C1-4alky substituted imidazol such as 1-methyl-1H-imidazol, azetidyl, tetrahydrofuranyl, dioxolanyl, imidazolidinyl, oxathiolanyl, oxazolidinyl, pyran, thiopyran, tetrahydropyran or tetrahydrothiopyran, thiophene, furan, pyrazoline, pyrimidine, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 3-pyrazinyl, 2-quinolyl, 3-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 2-quinazolinyl, 4-quinazolinyl, 2-quinoxalinyl, 1-phthalazinyl, 4-oxo-2-imidazolyl, 2-imidazolyl, 4-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 4-oxo-2-oxazolyl, 5-oxazolyl, 4,5,-dihydrooxazole, 1,2,3-oxathiole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazole, 4-isothiazole, 5-isothiazole, 2-indolyl, 3-indolyl, 3-indazolyl, 2-benzoxazolyl, 2-benzothiazolyl, 2-benzimidazolyl, 2-benzofuranyl, 3-benzofuranyl, benzoisothiazole, benzisoxazole, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 3-isopyrrolyl, 4-isopyrrolyl, 5-isopyrrolyl, 1,2,3,-oxathiazole-1-oxide, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 5-oxo-1,2,4-oxadiazol-3-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 3-oxo-1,2,4-thiadiazol-5-yl, 1,3,4-thiadiazol-5-yl, 2-oxo-1,3,4-thiadiazol-5-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1,2,3,4-tetrazol-5-yl, 5-oxazolyl, 1-pyrrolyl, 1-pyrazolyl, 1,2,3-triazol-1-yl, 1,2,4-triazol-1-yl, 1-tetrazolyl, 1-indolyl, 1-indazolyl, 2-isoindolyl, 7-oxo-2-isoindolyl,1-purinyl, 3-isothiazolyl, 4-isothiazolyl and 5-isothiazolyl, 1,3,4,-oxadiazole, 4-oxo-2-thiazolinyl, or 5-methyl-1,3,4-thiadiazol-2-yl, thiazoledione, 1,2,3,4-thiatriazole, 1,2,4-dithiazolone. Each of these moieties may be substituted as appropriate.
xe2x80x9cAmino acid,xe2x80x9d includes a residue of natural amino acid (e.g. Ala, Arg, Asn, Asp, Cys, Glu, Gln, Gly, His, Hyl, Hyp, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Val) in D or L form, as well as unnatural amino acids (e.g. phosphoserine, phosphothreonine, phosphotyrosine, hydroxyproline, gamma-carboxyglutamate; hippuric acid, octahydroindole-2-carboxylic acid, statine, 1,2,3,4,-tetrahydroisoquinoline-3-carboxylic acid, penicillamine, ornithine, citruline, -methyl-alanine, para-benzoylphenylalanine, phenylglycine, propargylglycine, sarcosine, and tert-butylglycine). An amino acid can conveniently be linked to the remainder of a compound of formula I through the carboxy terminus, the amino terminus, or through any other convenient point of attachment, such as, for example, through the sulfur of cysteine. In particular, an amino acid can conveniently be linked to the remainder of a compound of formula I through the carboxy terminus.
Mammal denotes human and animals, specifically including food animals and companion animals.
It will be appreciated by those skilled in the art that compounds of the invention have one or more achiral center and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism. It is to be understood that the present invention encompasses any racemic, optically-active, polymorphic, tautomeric, or stereoisomeric form, or mixture thereof, of a compound of the invention, which possesses the useful properties described herein, it being well known in the art how to prepare optically active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase) and how to determine antiviral activity using the standard tests described herein, or using other similar tests which are well known in the art.
The compounds of the present invention are generally named according to the IUPAC or CAS nomenclature system. Other nomenclature systems may also be used. Abbreviations which are well known to one of ordinary skill in the art may be used (e.g. xe2x80x9cPhxe2x80x9d for phenyl, xe2x80x9cMexe2x80x9d for methyl, xe2x80x9cEtxe2x80x9d for ethyl, xe2x80x9chxe2x80x9d for hour or hours and xe2x80x9crtxe2x80x9d for room temperature).
Specific and preferred values listed below for radicals, substituents, and ranges, are for illustration only; they do not exclude other defined values or other values within defined ranges for the radicals and substituents.
Specifically, the term xe2x80x9cC1-8alkyl,xe2x80x9d or xe2x80x9cC1-4alkylxe2x80x9d refers to an alkyl group having one to eight or one to four carbon atoms such as, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and their isomeric forms thereof.
Specifically, a 5- or 6-membered heterocyclic ring includes piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, Nxe2x80x94C1-4alky substituted piperazinyl such as 4-methyl piperazinyl, or pyrrolidinyl.
Specifically, a 5- or 6-membered heterocyclic ring includes pyridyl, imidazolyl, Nxe2x80x94C1-4alky substituted imidazol such as 1-methyl-1H-imidazol.
Specifically, R5 is C1-8alkyl substituted with OR7 or het.
Specifically, R5 is C1-4alkyl substituted with OH.
Specifically, R5 is C1-4alkyl substituted with het.
Specifically, het is morpholinyl or thiomorpholinyl.
Specifically, R5 is 4-morpholinylmethyl.
Specifically, R5 is C1-8alkyl, optionally substituted with OR9.
Specifically, R5 is C1-8alkyl which is partially unsaturated and optionally substituted with OR9.
Specifically, R5 is propynyl substituted with OH.
Specifically, R5 is 3-hydroxypropyl.
Specifically, R3 and R4 are independently hydrogen.
Specifically, R1 and R2 are independently hydrogen, fluoro, or C1-8 alkyl substituted with R6 or OR7.
Specifically, R1 and R2 are independently hydrogen, fluoro, C1-8 alkyl substituted with R6 or OR7; aryl, het, or R1 and R2 together with the carbon to which they are attached form a six-(6) membered cycloalkyl or a het; wherein R6 is het, SOiR8, OR8 or NR8R9; wherein R7 is P(xe2x95x90O)(OR10)2, CO(CH2)nCON(CH3)(CH2)nSO3xe2x88x92M+, or C(xe2x95x90O)C1-6alkyl, wherein R8 and R9 are independently hydrogen, aryl, het, or C1-8alkyl which is further optionally substituted with one or more aryl, het, halo, CO2R10, SOiR10, or OR10; wherein R10 is H or C1-4alkyl, optionally substituted with OH.
Specifically, R1 and R2 are independently H, C1-4alkyl substituted with OR8 wherein R8 is H, or C1-4alkylsubstituted with OR10.
Specifically, R1 is H; R2 is aryl wherein aryl is optionally substituted with one or two halo, CN, OR10, or C1-4alkylsubstituted with OR10.
Specifically, R1 is H; R2 is aryl wherein aryl is fused with a heterocyclic ring.
Specifically, R2 is 1,3-benzodioxolyl or 1,4-benxodioxinyl.
Specifically, R1 is H; R2 is het.
Specifically, het is a five-(5) or six-(6) membered saturated or unsaturated heterocyclic ring having 1, 2, or 3 heteroatoms selected from the group consisting of O, S, and NW, wherein W is hydrogen, C1-4alkyl, C(xe2x95x90O)OC1-4alkyl or absent, wherein het may be substituted with one or more halo, C1-4alkyl, CF3, oxo or oxine.
Specifically, het is pyridinyl.
Specifically, het is a five-(5) membered heterocyclic ring.
Specifically, R1 and R2 together with the carbon to which they are attached form a het, wherein het is a five-(5) or six-(6) membered heterocyclic ring having 1, 2, or 3 heteroatoms selected from the group consisting of O, S, and NW, wherein W is hydrogen, C1-4alkyl, or C(xe2x95x90O)OC1-4alkyl, wherein het may be substituted with one or more halo, OR10, C1-4alkyl, CF3, oxo or oxine; more specifically, het is a (6) membered heterocyclic ring; even more specifically, het is pyran, piperdine, or thiopyran.
Specifically, R1 and R2 together with the carbon to which they are attached form a six-(6) membered cycloalkyl; more specifically, cycloalkyl is optionally substituted with oxo, or OR10.
Specifically, R6 is het, SOiR8, OR8 or NR8R9.
Specifically, R7 is Pxe2x95x90O)(OH)2, (Pxe2x95x90O)(C1-4alkoxy)2, C(xe2x95x90O)C1-6alkyl, or CO(CH2)nCON(CH3)(CH2)nSO3xe2x88x92M+.
Specifically, R8 and R9 are independently hydrogen, aryl, het, or C1-8alkyl which is further optionally substituted with one or more aryl, het, halo, CO2R10, SOiR10, or OR10;
Specifically, R10 is H or C1-4alkyl, optionally substituted with OH.
Specifically, R2 is hydrogen, and R1 is C1-8 alkyl substituted with R6 or OR7; where R6 is het, SR8, OR8 or NR8R9; wherein R7 is (Pxe2x95x90O)(OCH3)2, CO(CH2)nCON(CH3)(CH2)nSO3xe2x88x92M+, or C(xe2x95x90O)CH3, R8 and R9 are independently hydrogen, het, or C1-8alkyl, which is optionally substituted with one or two het, CO2R10, SOR10, or OR10; R10 is H or C1-4alkyl, optionally substituted with OH.
Specifically, R11 is H, halo, or C1-4alkyl optionally substituted with one to three halo.
Specifically, R12 is H, SOiR8, OR8, C(xe2x95x90O)OR8, C(xe2x95x90O)R8, NR8R9; or C1-8alkyl, which may be partially unsaturated and optionally substituted with one to three N3, halo, CN, or R6.
Specifically, R11 and R12 are hydrogen.
Specifically, het is piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, Nxe2x80x94C1-4alky substituted piperazinyl, pyrrolidinyl, pyridyl, imidazolyl, or Nxe2x80x94C1-4alky substituted imidazol.
Specifically, R1, R2, R3 and R4 are independently hydrogen, hydroxymethyl, morpholinylmethyl, (pyridinylmethyl)aminomethyl, (dimethylamino)methyl, (hydroxyethyl)sulfanylmethyl, (1-methyl-1H-imidazol-2-yl)sulfanylmethyl, xe2x80x94CH2OCO(CH2)6CON(CH3)(CH2)2SO3xe2x88x92M+, xe2x80x94CH2OC(xe2x95x90O)CH3, (4-methyl-1-piperazinyl)methyl 1-pyrrolidinylmethyl, (2,3-dihydroxypropyl)aminomethyl, (2-hydroxyethyl)aminomethyl, 1-piperidinylmethyl, bis(2-hydroxyethyl)aminomethyl, 1H-imidazol-1-ylmethyl, (methylsulfanyl)methyl, (tert-butylsulfanyl)methyl, methylsulfanyl acetate, (2,3-dihydroxypropyl)sulfanylmethyl, phenyl, or fluoro. or CH2OP(xe2x95x90O)(OCH3)2.
Specifically, R1, R2, R3 and R4 are independently hydrogen, hydroxymethyl, morpholinylmethyl, (2-pyridinylmethyl)aminomethyl, (3-pyridinylmethyl)aminomethyl, (dimethylamino)methyl, (2-hydroxyethyl)sulfanylmethyl, (1-methyl-1H-imidazol-2-yl)sulfanylmethyl, xe2x80x94CH2OCO(CH2)6CON(CH3)(CH2)2SO3xe2x88x92M+, xe2x80x94CH2OC(xe2x95x90O)CH3, or CH2OP(xe2x95x90O)(OCH3)2.
Specifically, R1 and R2 are independently hydrogen, R3 and R4 are independently fluoro, phenyl, or C1-8 alkyl substituted with het or OH.
Specifically, R1 is hydrogen and R2 is het.
Specifically, R1 is hydrogen and R2 is 2-pyridinyl, 3-pyridinyl, or 4-pyridinyl.
Specifically, R3 and R4 are independently fluoro or hydroxymethyl.
Specifically, R3 is hydrogen and R4 is phenyl, morpholinylmethyl, or hydroxymethyl.
Specifically, R3 is morpholinylmethyl.
Specifically, a compound of formula I is the following structure I-A; 
Specifically, a compound of formula I is the following structure I-B; 
Specifically, a compound of formula I is the following structure I-C; 
Specifically, a compound of formula I is the following structure I-D; 
Specifically, a compound of formula I is the following structure I-E; 
Specifically, a compound of formula I is the following structure I-F; 
Specifically, a compound of formula I is the following structure I-G; 
Specifically, a compound of formula I is the following structure I-H; 
Specifically, a compound of formula I is the following structure I-I; 
Specifically, a compound of formula I is the following structure I-J; 
Specifically, a compound of formula I is the following structure I-K; 
Specifically, a compound of formula I is the following structure I-L; 
Specifically, a compound of formula I is the following structure I-M; 
Specifically, a compound of formula I is the following structure I-N; 
Specifically, a compound of formula I is the following structure I-O; 
Specifically, a compound of formula I is the following structure I-P; 
More specifically, Y is Cl in the formulas I-A to I-P. Examples of the compounds of the present invention are:
a) N-(4-Chlorobenzyl)-2-(hydroxymethyl)-9-(morpholin-4-ylmethyl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
b) N-(4-Chlorobenzyl)-2-(R or S)-(hydroxymethyl)-9-(morpholin-4-ylmethyl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
c) N-(4-Chlorobenzyl)-9-(morpholin-4-ylmethyl)-7-oxo-2-pyridin-3-yl-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
d) N-(4-Chlorobenzyl)-9-(morpholin-4-ylmethyl)-7-oxo-2-pyridin-4-yl-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
e) N-(4-Chlorobenzyl)-9-(morpholin-4-ylmethyl)-7-oxo-2-pyridin-2-yl-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
f) N-(4-Chlorobenzyl)-9-(morpholin-4-ylmethyl)-7-oxo-2-(R or S)-pyridin-3-yl-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
g) N-(4-Chlorobenzyl)-2,9-bis(morpholin-4-ylmethyl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
h) 2-[(tert-Butylsulfanyl)methyl]-N-(4-chlorobenzyl)-9-(morpholin-4-ylmethyl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
i) N-(4-Chlorobenzyl)-2-{[(2-hydroxyethyl)sulfanyl]methyl}-9-(morpholin-4-ylmethyl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
j) N-(4-Chlorobenzyl)-2-{[(1-methyl-1H-imidazol-2-yl)sulfanyl]methyl}-9-(morpholin-4-ylmethyl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
k) N-(4-Chlorobenzyl)-9-(morpholin-4-ylmethyl)-7-oxo-2-{[(3-pyridinylmethyl)amino]methyl}-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
l) [6-{[(4-Chlorobenzyl)amino]carbonyl}-9-(morpholin-4-ylmethyl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinolin-2-yl]methyl acetate,
m) N-(4-Chlorobenzyl)-9-(morpholin-4-ylmethyl)-7-oxo-2-(R or S)-{[(3-pyridinylmethyl)amino]methyl}-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
n) N-(4-Chlorobenzyl)-2-(3-hydroxyphenyl)-9-(morpholin-4-ylmethyl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
o) N-(4-Chlorobenzyl)-9-(morpholin-4-ylmethyl)-7-oxo-2-(R or S)-pyridin-2-yl-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
p) N-(4-Chlorobenzyl)-2-[3-(hydroxymethyl)phenyl]-9-(morpholin-4-ylmethyl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
q) N-(4-Chlorobenzyl)-2-[2-(hydroxymethyl)phenyl]-9-(morpholin-4-ylmethyl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
r) N-(4-Chlorobenzyl)-2-(1-methyl-1H-imidazol-2-yl)-9-(morpholin-4-ylmethyl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
s) N-(4-Chlorobenzyl)-2-(2-furyl)-9-(morpholin-4-ylmethyl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
t) N-(4-Chlorobenzyl)-2-(3-cyanophenyl)-9-(morpholin-4-ylmethyl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
u) N-(4-Chlorobenzyl)-2-(3-furyl)-9-(morpholin-4-ylmethyl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
v) N-(4-Chlorobenzyl)-9-(morpholin-4-ylmethyl)-7-oxo-2-thien-2-yl-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
w) N-(4-Chlorobenzyl)-2-(3,5-difluorophenyl)-9-(morpholin-4-ylmethyl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
x) 2-(1,3-Benzodioxol-5-yl)-N-(4-chlorobenzyl)-9-(morpholin-4-ylmethyl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
y) N-(4-Chlorobenzyl)-2-(2,3-dihydro-1,4-benzodioxin-6-yl)-9-(morpholin-4-ylmethyl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
z) 2-(1,3-Benzodioxol-4-yl)-N-(4-chlorobenzyl)-9-(morpholin-4-ylmethyl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
aa) 2-[3,5-bis(Methoxymethoxy)phenyl]-N-(4-chlorobenzyl)-9-(morpholin-4-ylmethyl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
bb) N-[(4-Chlorobenzyl)-9-(morpholin-4-ylmethyl)-7-oxo-2-thien-3-yl-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
cc) N-(4-Chlorobenzyl)-2,2-bis[(methoxymethoxy)methyl]-9-(morpholin-4-ylmethyl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
dd) N-[(4-Chlorophenyl)methyl]-9xe2x80x2-(4-morpholinylmethyl)-4,7xe2x80x2-dioxospiro[cyclohexane-1,2xe2x80x2(3xe2x80x2H)-[7H]pyrido[1,2,3-dr][1,4]benzoxazine]-6xe2x80x2-carboxamide,
ee) N-[(4-Chlorophenyl)methyl]-4-hydroxy-9xe2x80x2-(4-morpholinylmethyl)-7xe2x80x2-oxospiro[cyclohexane-1,2xe2x80x2(3xe2x80x2H)-[7H]pyrido[1,2,3-de][1,4]benzoxazine]-6xe2x80x2-carboxamide,
ff) N-(4-Chlorobenzyl)-3,9-bis(morpholin-4-ylmethyl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
gg) N-(4-Chlorobenzyl)-9-(morpholin-4-ylmethyl)-7-oxo-2-phenyl-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
hh) N-(4-Chlorobenzyl)-2,2-difluoro-9-(morpholin-4-ylmethyl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
ii) N-(4-Chlorobenzyl)-2-[(methylsulfanyl)methyl]-9-(morpholin-4-ylmethyl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
jj) N-(4-Chlorobenzyl)-2-[(dimethylamino)methyl]-9-(morpholin-4-ylmethyl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
kk) N-(4-Chlorobenzyl)-2-[(4-methyl-1-piperazinyl)methyl]-9-(morpholin-4-ylmethyl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
ll) Methyl ({[6-{[(4-chlorobenzyl)amino]carbonyl}-9-(morpholin-4-ylmethyl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinolin-2-yl]methyl}thio)acetate,
mm) N-(4-Chlorobenzyl)-9-(morpholin-4-ylmethyl)-7-oxo-2-(1-pyrrolidinylmethyl)-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
nn) N-(4-Chlorobenzyl)-2-{[(2,3-dihydroxypropyl)sulfanyl]methyl}-9-(morpholin-4-ylmethyl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
oo) N-(4-Chlorobenzyl)-2-{[(2,3-dihydroxypropyl)amino]methyl}-9-(morpholin-4-ylmethyl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
pp) N-(4-Chlorobenzyl)-2-{[(2-hydroxyethyl)amino]methyl}-9-(morpholin-4-ylmethyl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
qq) N-(4-Chlorobenzyl)-9-(morpholin-4-ylmethyl)-7-oxo-2-(1-piperidinylmethyl)-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
rr) 2-{[bis(2-Hydroxyethyl)amino]methyl}-N-(4-chlorobenzyl)-9-(morpholin-4-ylmethyl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
ss) N-(4-Chlorobenzyl)-9-(morpholin-4-ylmethyl)-7-oxo-2-{[(2-pyridinylmethyl)amino]methyl}-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
tt) 2-[(8-{[6-{[(4-Chlorobenzyl)amino]carbonyl}-9-(morpholin-4-ylmethyl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinolin-2-yl]methoxy}-8-oxooctanoyl)(methyl)amino]ethanesulfonic acid sodium salt,
uu) [6-{[(4-Chlorobenzyl)amino]carbonyl}-9-(morpholin-4-ylmethyl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinolin-2-yl]methyl dimethyl phosphate,
vv) N-(4-Chlorobenzyl)-9-(morpholin-4-ylmethyl)-7-oxo-2-{[(4-pyridinylmethyl)amino]methyl}-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
ww) N-(4-Chlorobenzyl)-2-(1H-imidazol-1-ylmethyl)-9-(morpholin-4-ylmethyl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
xx) N-(4-Chlorobenzyl)-2-{[(4-chlorobenzyl)amino]methyl}-9-(morpholin-4-ylmethyl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
yy) N-(4-Chlorobenzyl)-3-(hydroxymethyl)-9-(morpholin-4-ylmethyl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
zz) N-(4-Chlorobenzyl)-2-(4-hydroxyphenyl)-9-(morpholin-4-ylmethyl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
aaa) N-(4-Chlorobenzyl)-2-{3-[(methoxymethoxy)methyl]phenyl}-9-(morpholin-4-ylmethyl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
bbb) N-(4-Chlorobenzyl)-2-{2-[(methoxymethoxy)methyl]phenyl}-9-(morpholin-4-ylmethyl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
ccc) N-(4-Chlorobenzyl)-2-(2-hydroxyphenyl)-9-(morpholin-4-ylmethyl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
ddd) N-[(4-Chlorophenyl)methyl]-2,3,5,6-tetrahydro-9xe2x80x2-(4-morpholinylmethyl)-7xe2x80x2-oxospiro[4H-pyran-4,2xe2x80x2(3xe2x80x2H)-[7H]pyrido[1,2,3-de][1,4]benzoxazine]-6xe2x80x2-carboxamide,
eee) 1,1-Dimethylethyl6-[[[(4-chlorophenyl)methyl]amino]carbonyl]-9xe2x80x2-(4-morpholinylmethyl)-7xe2x80x2-oxospiro[piperidine-4,2xe2x80x2(3xe2x80x2H)-[7H]pyrido[1,2,3-de][1,4]benzoxazine]-1-carboxylate,
fff) N-[(4-Chlorophenyl)methyl]-9xe2x80x2-(4-morpholinylmethyl)-7xe2x80x2-oxospiro[piperidine-4,2xe2x80x2(3xe2x80x2H)-[7H]pyrido[1,2,3-de][1,4]benzoxazine]-6xe2x80x2-carboxamide,
ggg) N-(4-Chlorobenzyl)-2,2-bis(hydroxymethyl)-9-(morpholin-4-ylmethyl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
hhh) N-[(4-Chlorophenyl)methyl]-2xe2x80x2,3xe2x80x2,5xe2x80x2,6xe2x80x2-tetrahydro-9-(4-morpholinylmethyl)-7-oxospiro[7H-pyrido[1,2,3-de]-1,4-benzoxazine-2(3H),4xe2x80x2-[4H]thiopyran]-6-carboxamide,
iii) N-(4-Chlorobenzyl)-9-(morpholin-4-ylmethyl)-7-oxo-3-phenyl-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
jjj) N-(4-Chlorobenzyl)-3,3-bis(hydroxymethyl)-9-(3-hydroxy-1-propynyl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
kkk) N-(4-Chlorobenzyl)-3,3-bis(hydroxymethyl)-9-(3-hydroxypropyl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
lll) N-(4-Chlorobenzyl)-2-[2-(methoxymethoxy)phenyl]-9-(morpholin-4-ylmethyl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
mmm) N-(4-Chlorobenzyl)-2-{4-[(methoxymethoxy)methyl]phenyl}-9-(morpholin-4-ylmethyl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
nnn) 2-[2,3-bis(Methoxymethoxy)phenyl]-N-(4-chlorobenzyl)-9-(morpholin-4-ylmethyl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
ooo) N-[(4-Chlorophenyl)methyl]-1-methyl-9xe2x80x2-(4-morpholinylmethyl)-7xe2x80x2-oxospiro[-piperidine4,2xe2x80x2(3xe2x80x2H)-[7H]pyrido[1,2,3-de][1,4]benzoxazine]-6xe2x80x2-carboxamide, or
ppp) N-[(4-Chlorophenyl)methyl]-9xe2x80x3-(4-morpholinylmethyl)dispiro[1,3-dioxolane-2,1xe2x80x2-cyclohexane-4xe2x80x2,2xe2x80x3(3xe2x80x3H)-[7H]pyrido[1,2,3-de][1,4]benzoxazine]-6xe2x80x3-carboxamide.
Additional examples of the compounds of the present invention are:
a) N-(4-Chlorobenzyl)-2-(hydroxymethyl)-9-(morpholin-4-ylmethyl)-7-thioxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
b) N-(4-Chlorobenzyl)-2-(R or S)-(hydroxymethyl)-9-(morpholin-4-ylmethyl)-7-thioxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
c) N-(4-Chlorobenzyl)-9-(morpholin-4-ylmethyl)-7-thioxo-2-pyridin-3-yl-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
d) N-(4-Chlorobenzyl)-9-(morpholin-4-ylmethyl)-7-thioxo-2-pyridin-4-yl-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
e) N-(4-Chlorobenzyl)-9-(morpholin-4-ylmethyl)-7-thioxo-2-pyridin-2-yl-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
f) N-(4-Chlorobenzyl)-9-(morpholin-4-ylmethyl)-7-thioxo-2-(R or S)-pyridin-3-yl-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
g) N-(4-Chlorobenzyl)-2,9-bis(morpholin-4-ylmethyl)-7-thioxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
h) 2-[(tert-Butylsulfanyl)methyl]-N-(4-chlorobenzyl)-9-(morpholin-4-ylmethyl)-7-thioxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
i) N-(4-Chlorobenzyl)-2-{[(2-hydroxyethyl)sulfanyl]methyl}-9-(morpholin-4-ylmethyl)-7-thioxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
j) N-(4-Chlorobenzyl)-2-{[(1-methyl-1H-imidazol-2-yl)sulfanyl]methyl}-9-(morpholin-4-ylmethyl)-7-thioxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
k) N-(4-Chlorobenzyl)-9-(morpholin-4-ylmethyl)-7-thioxo-2-{[(3-pyridinylmethyl)amino]methyl}-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
l) [6-{[(4-Chlorobenzyl)amino]carbonyl}-9-(morpholin-4-ylmethyl)-7-thioxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinolin-2-yl]methyl acetate,
m) N-(4-Chlorobenzyl)-9-(morpholin-4-ylmethyl)-7-thioxo-2-(R or S)-{[(3-pyridinylmethyl)amino]methyl}-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
n) N-(4-Chlorobenzyl)-2-(3-hydroxyphenyl)-9-(morpholin-4-ylmethyl)-7-thioxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
o) N-(4-Chlorobenzyl)-9-(morpholin-4-ylmethyl)-7-thioxo-2-(R or S)-pyridin-2-yl-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
p) N-(4-Chlorobenzyl)-2-[3-(hydroxymethyl)phenyl]-9-(morpholin-4-ylmethyl)-7-thioxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
q) N-(4-Chlorobenzyl)-2-[2-(hydroxymethyl)phenyl]-9-(morpholin-4-ylmethyl)-7-thioxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
r) N-(4-Chlorobenzyl)-2-(1-methyl-1H-imidazol-2-yl)-9-(morpholin-4-ylmethyl)-7-thioxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
s) N-(4-Chlorobenzyl)-2-(2-furyl)-9-(morpholin-4-ylmethyl)-7-thioxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
t) N-(4-Chlorobenzyl)-2-(3-cyanophenyl)-9-(morpholin-4-ylmethyl)-7-thioxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
u) N-(4-Chlorobenzyl)-2-(3-furyl)-9-(morpholin-4-ylmethyl)-7-thioxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
v) N-(4-Chlorobenzyl)-9-(morpholin-4-ylmethyl)-7-thioxo-2-thien-2-yl-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
w) N-(4-Chlorobenzyl)-2-(3,5-difluorophenyl)-9-(morpholin-4-ylmethyl)-7-thioxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
x) 2-(1,3-Benzodioxol-5-yl)-N-(4-chlorobenzyl)-9-(morpholin-4-ylmethyl)-7-thioxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
y) N-(4-Chlorobenzyl)-2-(2,3-dihydro-1,4-benzodioxin-6-yl)-9-(morpholin-4-ylmethyl)-7-thioxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
z) 2-(1,3-Benzodioxol-4-yl)-N-(4-chlorobenzyl)-9-(morpholin-4-ylmethyl)-7-thioxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
aa) 2-[3,5-bis(Methoxymethoxy)phenyl]-N-(4-chlorobenzyl)-9-(morpholin-4-ylmethyl)-7-thioxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
bb) N-(4-Chlorobenzyl)-9-(morpholin-4-ylmethyl)-7-thioxo-2-thien-3-yl-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
cc) N-(4-Chlorobenzyl)-2,2-bis[(methoxymethoxy)methyl]-9-(morpholin-4-ylmethyl)-7-thioxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
dd) N-[(4-Chlorophenyl)methyl]-9xe2x80x2-(4-morpholinylmethyl)-4-oxo-7xe2x80x2-thioxospiro[cyclohexane-1,2xe2x80x2(3xe2x80x2H)-[7H]pyrido[1,2,3-de][1,4]benzoxazine]-6xe2x80x2-carboxamide,
ee) N-[(4-Chlorophenyl)methyl]-4-hydroxy-9xe2x80x2-(4-morpholinylmethyl)-7xe2x80x2-thioxospiro[cyclohexane-1,2xe2x80x2(3xe2x80x2H)-[7H]pyrido[1,2,3-de][1,4]benzoxazine]-6xe2x80x2-carboxamide,
ff) N-(4-Chlorobenzyl)-3,9-bis(morpholin-4-ylmethyl)-7-thioxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
gg) N-(4-Chlorobenzyl)-9-(morpholin-4-ylmethyl)-7-thioxo-2-phenyl-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
hh) N-(4-Chlorobenzyl)-2,2-difluoro-9-(morpholin-4-ylmethyl)-7-thioxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
ii) N-(4-Chlorobenzyl)-2-[(methylsulfanyl)methyl]-9-(morpholin-4-ylmethyl)-7-thioxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
jj) N-(4-Chlorobenzyl)-2-[(dimethylamino)methyl]-9-(morpholin-4-ylmethyl)-7-thioxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
kk) N-(4-Chlorobenzyl)-2-[(4-methyl-1-piperazinyl)methyl]-9-(morpholin-4-ylmethyl)-7-thioxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
ll) Methyl ({[6-{[(4-chlorobenzyl)amino]carbonyl}-9-(morpholin-4-ylmethyl)-7-thioxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinolin-2-yl]methyl}thio)acetate,
mm) N-(4-Chlorobenzyl)-9-(morpholin-4-ylmethyl)-7-thioxo-2-(1-pyrrolidinylmethyl)-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
nn) N-(4-Chlorobenzyl)-2-{[(2,3-dihydroxypropyl)sulfanyl]methyl}-9-(morpholin-4-ylmethyl)-7-thioxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
oo) N-(4-Chlorobenzyl)-2-{[(2,3-dihydroxypropyl)amino]methyl }-9-(morpholin-4-ylmethyl)-7-thioxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
pp) N-(4-Chlorobenzyl)-2-{[(2-hydroxyethyl)amino]methyl}-9-(morpholin-4-ylmethyl)-7-thioxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
qq) N-(4-Chlorobenzyl)-9-(morpholin-4-ylmethyl)-7-thioxo-2-(1-piperidinylmethyl)-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
rr) 2-{[bis(2-Hydroxyethyl)amino]methyl}-N-(4-chlorobenzyl)-9-(morpholin-4-ylmethyl)-7-thioxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
ss) N-(4-Chlorobenzyl)-9-(morpholin-4-ylmethyl)-7-thioxo-2-{[(2-pyridinylmethyl)amino]methyl}-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
tt) 2-[(8-{[6-{[(4-Chlorobenzyl)amino]carbonyl}-9-(morpholin-4-ylmethyl)-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinolin-2-yl]methoxy}-8-oxooctanoyl)(methyl)amino]ethanesulfonic acid sodium salt,
uu) [6-{[(4-Chlorobenzyl)amino]carbonyl}-9-(morpholin-4-ylmethyl)-7-thioxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinolin-2-yl]methyl dimethyl phosphate,
vv) N-(4-Chlorobenzyl)-9-(morpholin-4-ylmethyl)-7-thioxo-2-{[(4-pyridinylmethyl)amino]methyl}-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
ww) N-(4-Chlorobenzyl)-2-(1H-imidazol-1-ylmethyl)-9-(morpholin-4-ylmethyl)-7-thioxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
xx) N-(4-Chlorobenzyl)-2-{[(4-chlorobenzyl)amino]methyl}-9-(morpholin-4-ylmethyl)-7-thioxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
yy) N-(4-Chlorobenzyl)-3-(hydroxymethyl)-9-(morpholin-4-ylmethyl)-7-thioxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
zz) N-(4-Chlorobenzyl)-2-(4-hydroxyphenyl)-9-(morpholin-4-ylmethyl)-7-thioxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
aaa) N-(4-Chlorobenzyl)-2-{3-[(methoxymethoxy)methyl]phenyl}-9-(morpholin-4-ylmethyl)-7-thioxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
bbb) N-(4-Chlorobenzyl)-2-{2-[(methoxymethoxy)methyl]phenyl}-9-(morpholin-4-ylmethyl)-7-thioxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
ccc) N-(4-Chlorobenzyl)-2-(2-hydroxyphenyl)-9-(morpholin-4-ylmethyl)-7-thioxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
ddd) N-[(4-Chlorophenyl)methyl]-2,3,5,6-tetrahydro-9xe2x80x2-(4-morpholinylmethyl)-7xe2x80x2-thioxospiro[4H-pyran-4,2xe2x80x2(3xe2x80x2H)-[7H]pyrido[1,2,3-de][1,4]benzoxazine]-6xe2x80x2-carboxamide,
eee) 1,1-Dimethylethyl 6-[[[(4-chlorophenyl)methyl]amino]carbonyl]-9xe2x80x2-(4-morpholinylmethyl)-7xe2x80x2-thioxospiro[piperidine-4,2xe2x80x2(3xe2x80x2H)-[7H]pyrido[1,2,3-de][1,4]benzoxazine]-1-carboxylate,
fff) N-[(4-Chlorophenyl)methyl]-9xe2x80x2-(4-morpholinylmethyl)-7xe2x80x2-thioxospiro[piperidine-4,2xe2x80x2(3xe2x80x2H)-[7H]pyrido[1,2,3-de][1,4]benzoxazine]-6xe2x80x2-carboxamide,
ggg) N-(4-Chlorobenzyl)-2,2-bis(hydroxymethyl)-9-(morpholin-4-ylmethyl)-7-thioxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
hhh) N-[(4-Chlorophenyl)methyl]-2xe2x80x2,3xe2x80x2,5xe2x80x2,6xe2x80x2-tetrahydro-9-(4-morpholinylmethyl)-7-thioxospiro[7H-pyrido[1,2,3-de]-1,4-benzoxazine-2(3H),4xe2x80x2-[4H]thiopyran]-6-carboxamide,
iii) N-(4-Chlorobenzyl)-9-(morpholin-4-ylmethyl)-7-thioxo-3-phenyl-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
jjj) N-(4-Chlorobenzyl)-3,3-bis(hydroxymethyl)-9-(3-hydroxy-1-propynyl)-7-thioxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
kkk) N-(4-Chlorobenzyl)-3,3-bis(hydroxymethyl)-9-(3-hydroxypropyl)-7-thioxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
lll) N-(4-Chlorobenzyl)-2-[2-(methoxymethoxy)phenyl]-9-(morpholin-4-ylmethyl)-7-thioxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
mmm) N-(4-Chlorobenzyl)-2-{4-[(methoxymethoxy)methyl]phenyl}-9-(morpholin-4-ylmethyl)-7-thioxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
nnn) 2-[2,3-bis(Methoxymethoxy)phenyl]-N-(4-chlorobenzyl)-9-(morpholin-4-ylmethyl)-7-thioxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide,
ooo) N-[(4-Chlorophenyl)methyl]-1-methyl-9xe2x80x2-(4-morpholinylmethyl)-7xe2x80x2-thioxospiro[piperidine-4,2xe2x80x2(3xe2x80x2H)-[7H]pyrido[1,2,3-de][1,4]benzoxazine]-6xe2x80x2-carboxamide, or a pharmaceutically acceptable salt.
Additional examples of the compounds of the present invention are:
a) N-(4-Chlorobenzyl)-2-(hydroxymethyl)-9-(morpholin-4-ylmethyl)-7-thioxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxthioamide,
b) N-(4-Chlorobenzyl)-2-(R or S)-(hydroxymethyl)-9-(morpholin-4-ylmethyl)-7-thioxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxthioamide,
c) N-(4-Chlorobenzyl)-9-(morpholin-4-ylmethyl)-7-thioxo-2-pyridin-3-yl-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxthioamide,
d) N-(4-Chlorobenzyl)-9-(morpholin-4-ylmethyl)-7-thioxo-2-pyridin-4-yl-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxthioamide,
e) N-(4-Chlorobenzyl)-9-(morpholin-4-ylmethyl)-7-thioxo-2-pyridin-2-yl-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxthioamide,
f) N-(4-Chlorobenzyl)-9-(morpholin-4-ylmethyl)-7-thioxo-2-(R or S)-pyridin-3-yl-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxthioamide,
g) N-(4-Chlorobenzyl)-9-(morpholin-4-ylmethyl)-7-thioxo-2-(R or S)-pyridin-2-yl-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxthioamide, or a pharmaceutically acceptable salt.
Additional examples of the compounds of the present invention are:
a) N-(4-Chlorobenzyl)-2-(hydroxymethyl)-9-(morpholin-4-ylmethyl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxthioamide,
b) N-(4-Chlorobenzyl)-2-(R or S)-(hydroxymethyl)-9-(morpholin-4-ylmethyl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxthioamide,
c) N-(4-Chlorobenzyl)-9-(morpholin-4-ylmethyl)-7-oxo-2-pyridin-3-yl-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxthioamide,
d) N-(4-Chlorobenzyl)-9-(morpholin-4-ylmethyl)-7-oxo-2-pyridin-4-yl-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxthioamide,
e) N-(4-Chlorobenzyl)-9-(morpholin-4-ylmethyl)-7-oxo-2-pyridin-2-yl-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxthioamide,
f) N-(4-Chlorobenzyl)-9-(morpholin-4-ylmethyl)-7-oxo-2-(R or S)-pyridin-3-yl-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxthioamide,
g) N-(4-Chlorobenzyl)-9-(morpholin-4-ylmethyl)-7-oxo-2-(R or S)-pyridin-2-yl-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxthioamide, or a pharmaceutically acceptable salt.
The following Charts A-N describe the preparation of the compounds of formula I of the present invention. All of the starting materials are prepared by procedures described in these charts, by procedures well known to one of ordinary skill in organic chemistry or can be obtained commercially. All of the final compounds of the present invention are prepared by procedures described in these charts or by procedures analogous thereto, which would be well known to one of ordinary skill in organic chemistry. All of the variables used in the charts are as defined below or as in the formula I above.
As shown in CHART A, acid A-1, which is 3-hydroxy-4-nitrobenzoic acid, is reacted with thionyl chloride to give the corresponding acid chloride, which is treated with morpholine to provide amide A-2. Reduction of the nitro group using hydrogen gas and palladium catalyst gives aminophenol A-3, which is alkylated using sodium hydride and diethyl chloromalonate in dimethylformamide to give lactam A-4. Simultaneous reduction of the three carbonyl groups using borane-methyl sulfide in tetrahydrofuran affords amine A-5. Treatment of the amine with diethyl ethoxymethylenemalonate provides A-6, which is derivatized to acetate A-7 using acetic anhydride and pyridine. Cyclization to A-8 is effected by phosphorus pentoxide in methanesulfonic acid. Treatment of A-8 with p-chlorobenzylamine at 150xc2x0 C. cleaves the acetate and aminolyzes the ester, giving amide A-9. The alcohol is reacted with methanesulfonyl chloride and 2,4,6-collidine to give the intermediate mesylate A-10, which is subsequently reacted with a nucleophile of formulaxe2x80x94R8R9NH, R8SH or R8OH (wherein R8 and R9 are defined previously), or anions thereof, to provide compounds of formula A-11 wherein R6 is SOiR8, OR8, NR8R9, aryl, or het. 
As shown in CHART B, compound A-8, which is a racemic mixture, is resolved into its component enantiomers B-1a and B-1b by preparative chiral HPLC. The individual isomers are carried forth separately through Formulae B-2 and B-3, according to the protocol described for Chart A. 
As shown in CHART C, alcohol of Formula A-9 is reacted with acetic anhydride to provide acetate C-1. Alternately, the alcohol can be coupled with a salt of suleptanic acid, which is 8-[Methyl(2-sulfoethyl)amino]-8-oxooctanoic acid, using diisopropylcarbodiimide to afford C-2. Alternately, C-9 can be reacted sequentially with phosphorus oxychoride and then methanol to provide phosphate C-3.
As shown in CHART D, aminophenol of Formula A-3 is treated with methyl xcex1-bromophenylacetate and potassium carbonate in refluxing acetone to afford D-1. Reduction of the carbonyl groups using lithium aluminum hydride provides amine D-2, which is reacted with diethyl ethoxymethylenemalonate to furnish D-3. Cyclization to D-4 is effected with polyphosphoric acid, and aminolysis of the ester using p-chlorobenzylamine at 150xc2x0 C. affords compound D-5. 
As shown in CHART E, aminophenol of Formula A-3 is treated with ethyl bromodifluoroacetate and sodium hydride in dimethylformamide to afford E-1. Reduction of the carbonyl groups using lithium aluminum hydride provides amine E-2, which is reacted with diethyl ethoxymethylenemalonate to furnish E-3. Cyclization to E-4 is effected with polyphosphoric acid, and aminolysis of the ester using p-chlorobenzylamine at 150xc2x0 C. affords compound E-5. 
As shown in CHART F, nitrophenol of Formula A-2 is alkylated using phenacyl bromide and tetrabutylammonium bisulfate as a phase transfer catalyst, giving compound F-1. Reduction of the nitro group with tin(II) chloride is followed by spontaneous cyclization to enamine F-2. Reduction of the enamine with sodium borohydride furnishes F-3, which is further reduced using lithium aluminum hydride to afford amine F-4. Reaction with diethyl ethoxymethylenemalonate provides F-5, which is cyclized using polyphosphoric acid to give F-6. Aminolysis of the ester using p-chlorobenzylamine at 150xc2x0 C. affords compound F-7.
As shown in CHART G, nitro ketone of Formula A-2 is reacted with epichlorohydrin in the presence of sodium hydroxide to give epoxide G1. Reaction of the epoxide with morpholine in refluxing methanol provides amino alcohol G-2. The alcohol is oxidized with dimethyl sulfoxide and trifluoroacetic anhydride, and the resulting ketone is immediately hydrogenated using hydrogen gas and Raney nickel catalyst to give G-3. Reduction of the remaining keto group is accomplished with lithium aluminum hydride, affording amine G4. Treatment of the amine with diethyl ethoxymethylenemalonate, followed by polyphosphoric acid mediated cyclization of the intermediate enamine, provides compound G-5. Aminolysis of the ester using p-chlorobenzylamine at 150xc2x0 C. provides compound G-6.
As shown in CHART H, iodination of commercially available 2,3-difluorobenzoic acid H-1 using N-iodosuccinimide in trifluoromethanesulfonic acid provides trihalo-acid H-2. The acid is reacted with carbonyldiimidazole to form the intermediate acyl imidazolide, which is treated with ethyl trimethylsilyl malonate and 1,8-diazabicyclo[5.4.0]undec-7-ene to provide xcex2-ketoester H-3. Compound H-3 is reacted with triethyl orthoformate and acetic acid, followed by tris(hydroxymethyl) methylamine to afford triol H-4. Cyclization is effected using potassium carbonate in DMF, giving tricycle H-5, and aminolysis using p-chlorobenzylamine at 150xc2x0 C. affords H-6. The hydroxyl groups are masked as tert-butyldimethylsilyl ethers by reaction of the diol with tert-butyldimethylsilyl chloride and imidazole in dimethylformamide, giving H-7. Coupling of the iodide with propargyl alcohol using catalytic bis(triphenylphosphine)palladium (II) dichloride and copper (I) iodide provides H-8. Removal of the silyl ethers using hydrochloric acid in ethanol affords compound H-9. Alternately, the triple bond in H-8 is reduced with hydrogen gas and catalytic platinum on carbon to afford H-10, which is desilylated using hydrochloric acid in ethanol to provide compound H-11.
As shown in CHART I, treatment of xcex2-ketoester H-3 (Chart H) with triethyl orthoformate in refluxing acetic anhydride forms intermediate enol I-1, which then reacts with amino alcohols I-7 to provide enamines I-2. In Chart I, substitutent T refers to either a het or an aryl group. In some cases, groups T in Chart I may contain functional groups which are protected by suitable protective groups, such as methoxymethyl or tert-butyldimethylsilyl during the course of the synthesis. The protective groups are installed and then removed at the end of the synthesis using methods known to those skilled the art. Cyclization of the enamines to tricycles I-3 is accomplished using cesium carbonate in DMF. Aminolysis of the ethyl ester using neat p-chlorobenzylamine affords amides I-4. The iodide is converted to the aldehyde I-5 using carbon monoxide and tri-n-butylstannane under palladium catalysis. Finally, reductive amination of the aldehyde provides I-6.
Amino alcohols I-7 required for the sequence are prepared in two steps from the corresponding aldehydes I-8, by treatment of the aldehyde with trimethylsilyl cyanide and subsequent reduction of the TMS cyanohydrin with lithium aluminum hydride. 
CHART J illustrates a method for converting oxazinoquinolones to thioxazinoquinolones. 
A morpholino substituted 7-thioxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide, A-11, in a suitable solvent such as toluene and dichloroethane can be reacted with Lawesson""s reagent in the presence of KHMDS. The mixture is then reacted at a suitable temperature range providing the desired thioketone J-1.
CHART K provides an alternative method to convert oxazinoquinolones to thioxazinoquinolones when they are substituted with one or more alkyl hydroxy groups. For example, reacting compound H-11 in DMF with TIPSCl in the presence of imidiazole provides K-1 (See Wuts, P. G. Protecting Groups in Organic Chemistry 1999, 123). Next, ketone K-1 is reacted with Lawesson""s reagent in the presence of KHMDS in refluxing toluene and dichloroethane provides the thioketone K-2. The protected alcohol K-2 is then treated with Bu4N+Fxe2x88x92 in THF affording the hydroxyl compound K-3 (In Wuts, P. G. Protecting Groups in Organic Chemistry 1999, 124). 
CHART L illustrates a method for converting oxazinoquinolones to thioxazinoquinolone thioamides. A morpholino substituted 7-thioxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide, A-11, in a suitable solvent such as toluene and dichloroethane can be reacted with excess Lawesson""s reagent. The mixture is then reacted at a suitable temperature range providing the desired thioketone L-1.
As shown in CHART M, commercially available 2-fluoro-4-iodoaniline of Formula M-1 is reacted with diethyl ethoxymethylenemalnoate under thermal conditions to give the substituted 4-hydroxyquinoline of Formula M-2. Aminolysis of the ethyl ester using p-chlorobenzylamine under thermal conditions provides amide M-3. Palladium catalyzed formylation of the iodide affords aldehyde M-4, which is treated with morpholine and sodium triacetoxyborohydride to furnish amine M-5. Compound M-5 is reacted with various epoxides M-7, using cesium carbonate or calcium ethoxide as base, to provide compounds M-8 or M-9. Where not commercially available, epoxides M-7 may be prepared by treatment of the corresponding carbonyl compounds M-6 with trimethylsulfonium methylsulfate and sodium hydroxide. Epoxides M-7 may also be prepared by other routes familiar to those skilled in the art; for example, by epoxidation of the corresponding olefins. If epoxides M-7 are prepared in optically enriched form, either by synthesis or resolution, the resulting products M-8 and M-9 will also be obtained in optically enriched form. This method for the preparation of the compounds of the present invention is further illustrated in the Preparation 46 and Examples 36-54.
In CHART N, hydroxyalkylbenzyl alcohols N-1 are protected with an appropriate blocking group, such as methoxymethyl or tert-butyldimethylsilyl, giving monoprotected alcohols N-2. Oxidation of the remaining hydroxyl group provides aldehydes N-3. Where hydroxyalkylbenzaldehydes N-4 are commercially available, they may be converted to compounds N-3 using similar protection chemistry. Addition of trimethylsilyl cyanide provides amino alcohols N-5, which are carried forth through the sequence N-6, N-7, N-8, N-9, and N-10 as described for Chart I. Finally, the protecting group is removed from compounds N-10 using standard conditions familiar to those proficient in the art, for example, by treatment with acid in ethanol, to give compounds N-11. 
It will be apparent to those skilled in the art that the described synthetic procedures are merely representative in nature and alternative synthetic processes are known to one of ordinary skill in organic chemistry.
The inventive compounds may be used in their native form or as salts. In cases where compounds are sufficiently basic or acidic to form stable nontoxic acid or base salts, administration of the compounds as salts may be appropriate. Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, etoglutarate, and glycerophosphate. Suitable inorganic salts may also be formed, including hydrochloride, hydrobromide, sulfate, nitrate, bicarbonate, and carbonate salts.
Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion. Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made.
xe2x80x9cPharmaceutically acceptable saltsxe2x80x9d refers to those salts which possess the biological effectiveness and properties of the parent compound and which are not biologically or otherwise undesirable.
Compounds of the present invention can conveniently be administered in a pharmaceutical composition containing the compound in combination with a suitable excipient, the composition being useful in combating viral infections. Pharmaceutical compositions containing a compound appropriate for antiviral use are prepared by methods and contain excipients which are well known in the art. A generally recognized compendium of such methods and ingredients is Remington""s Pharmaceutical Sciences by E. W. Martin (Mark Publ. Co., 5th Ed., 1975).
The compounds and compositions of the present invention can be administered parenterally (for example, by intravenous, intraperitoneal or intramuscular injection), topically, orally, or rectally, depending on whether the preparation is used to treat internal or external viral infections.
For oral therapeutic administration, the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations should contain at least 0.1% of active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form. The amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained.
The tablets, troches, pills, capsules, and the like may also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules may be coated with gelatin, wax, shellac or sugar and the like. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed. In addition, the active compound may be incorporated into sustained-release preparations and devices.
The compounds or compositions can also be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
Pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. In all cases, the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.
For topical administration, the present compounds may be applied in pure form, i.e., when they are liquids. However, it will generally be desirable to administer them to the skin as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be a solid or a liquid.
Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like. Useful liquid carriers include water, alcohols or glycols or water-alcohol/glycol blends, in which the present compounds can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants. Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use. The resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers. Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user.
Examples of useful dermatological compositions which can be used to deliver the compounds of formula I to the skin are known to the art; for example, see Jacquet et al. (U.S. Pat. No. 4,608,392), Geria (U.S. Pat. No. 4,992,478), Smith et al. (U.S. Pat. No. 4,559,157) and Wortzman (U.S. Pat. No. 4,820,508).
Useful dosages of the compounds of formula I can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat. No. 4,938,949.
The compound is conveniently administered in unit dosage form; for example, containing 5 to 1000 mg, conveniently 10 to 750 mg, most conveniently, 50 to 500 mg of active ingredient per unit dosage form. The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye.
For internal infections, the compositions can be administered orally or parenterally at dose levels, calculated as the free base, of about 0.1 to 300 mg/kg, preferably 1.0 to 30 mg/kg of mammal body weight, and can be used in man in a unit dosage form, administered one to four times daily in the amount of 1 to 1000 mg per unit dose.
For parenteral administration or for administration as drops, as for eye infections, the compounds are presented in aqueous solution in a concentration of from about 0.1 to about 10%, more preferably about 0.1 to about 7%. The solution may contain other ingredients, such as emulsifiers, antioxidants or buffers.
Generally, the concentration of the compound(s) of formula I in a liquid composition, such as a lotion, will be from about 0.1-25 wt-%, preferably from about 0.5-10 wt-%. The concentration in a semi-solid or solid composition such as a gel or a powder will be about 0.1-5 wt-%, preferably about 0.5-2.5 wt-%.
The exact regimen for administration of the compounds and compositions disclosed herein will necessarily be dependent upon the needs of the individual subject being treated, the type of treatment and, of course, the judgment of the attending practitioner.
The exact regimen for administration of the compounds and compositions disclosed herein will necessarily be dependent upon the needs of the individual subject being treated, the type of treatment and, of course, the judgment of the attending practitioner. The compounds of the present invention can be administered to an animal in need of treatment. In most instances, this will be a human being, but the treatment of livestock and companion animals is also specifically contemplated as falling within the scope of the instant invention.
The antiviral activity of a compound of the invention can be determined using pharmacological models which are well known to the art, or using Test A described below.
The compounds of formula (I) and pharmaceutically acceptable salts thereof are useful as antiviral agents. Thus, they are useful to combat viral infections in animals, including man. The compounds are generally active against herpes viruses, and are particularly useful against the varicella zoster virus, the Epstein-Barr virus, the herpes simplex virus, the human herpes virus type 8 (HHV-8) and the cytomegalovirus (CMV).
While many of the compounds of the present invention have shown activity against the CMV polymerase, these compounds may be active against the cytomegalovirus by this or other mechanisms of action. Thus, the description below of these compounds"" activity against the CMV polymerase is not meant to limit the present invention to a specific mechanism of action.
The HCMV polymerase assay is performed using a scintillation proximity assay (SPA) as described in several references, such as N. D. Cook, et al., Pharmaceutical Manufacturing International, pages 49-53 (1992); K. Takeuchi, Laboratory Practice, September issue (1992); U.S. Pat. No. 4,568,649 (1986); which are incorporated by reference herein. Reactions are performed in 96-well plates. The assay is conducted in 100 xcexcl volume with 5.4 mM HEPES (pH 7.5), 11.7 mM KCl, 4.5 mM MgCl2, 0.36 mg/ml BSA, and 90 nM 3H-dTTP. Assays are run with and without CHAPS, (3-[(3-Cholamidopropyl)-dimethylammonio]-1-propane-sulfonate) at a final concentration of 2 mM. HCMV polymerase is diluted in enzyme dilution buffer containing 50% glycerol, 250 mM NaCl, 10 mM HEPES (pH 7.5), 100 xcexcg/ml BSA, and 0.01% sodium azide. The HCMV polymerase, which is expressed in recombinant baculovirus-infected SF-9 cells and purified according to literature procedures, is added at 10% (or 10 xcexcl) of the final reaction volume, i.e., 100 xcexcl. Compounds are diluted in 50% DMSO and 10 xcexcl are added to each well. Control wells contain an equivalent concentration of DMSO. Unless noted otherwise, reactions are initiated via the addition of 6 nM biotinylated poly(dA)-oligo(dT) template/primer to reaction mixtures containing the enzyme, substrate, and compounds of interest. Plates are incubated in a 25 C. or 37 C. H2O bath and terminated via the addition of 40 xcexcl/reaction of 0.5 M EDTA (pH 8) per well. Reactions are terminated within the time-frame during which substrate incorporation is linear and varied depending upon the enzyme and conditions used, i.e., 30 min. for HCMV polymerase. Ten xcexcl of streptavidin-SPA beads (20 mg/ml in PBS/10% glycerol) are added following termination of the reaction. Plates are incubated 10 min. at 37 C., then equilibrated to room temperature, and counted on a Packard Topcount. Linear regressions are performed and IC50""s are calculated using computer software.
A modified version of the above HCMV polymerase assay is performed as described above, but with the following changes: Compounds are diluted in 100% DMSO until final dilution into assay buffer. In the previous assay, compounds are diluted in 50% DMSO. 4.5 mM dithiotherotol (DTT) is added to the polymerase buffer. Also, a different lot of CMV polymerase is used, which appears to be more active resulting in a more rapid polymerase reaction. Results of the testing of representative compounds of formula I in this assay are shown in Table 1 below.
The symbol xe2x80x9c--xe2x80x9d refers to the data are not determined.
The compounds and their preparation of the present invention will be better understood in connection with the following Examples, which are intended as an illustration of and not a limitation upon the scope of the invention.